title: Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death.
abstract: Nuclear fragmentation is a common feature in many neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we show that nuclear lamina dispersion is an early and irreversible trigger for cell death initiated by deregulated Cdk5, rather than a consequence of apoptosis. Cyclin-dependent kinase 5 (Cdk5) activity is significantly increased in AD and contributes to all three hallmarks: neurotoxic amyloid-β (Aβ), neurofibrillary tangles (NFT), and extensive cell death. Using Aβ and glutamate as the neurotoxic stimuli, we show that deregulated Cdk5 induces nuclear lamina dispersion by direct phosphorylation of lamin A and lamin B1 in neuronal cells and primary cortical neurons. Phosphorylation-resistant mutants of lamins confer resistance to nuclear dispersion and cell death on neurotoxic stimulation, highlighting this as a major mechanism for neuronal death. Rapid alteration of lamin localization pattern and nuclear membrane change are further supported by in vivo data using an AD mouse model. After p25 induction, the pattern of lamin localization was significantly altered, preceding neuronal death, suggesting that it is an early pathological event in p25-inducible transgenic mice. Importantly, lamin dispersion is coupled with Cdk5 nuclear localization, which is highly neurotoxic. Inhibition of nuclear dispersion rescues neuronal cells from cell death, underscoring the significance of this event to Cdk5-mediated neurotoxicity.
authors.affiliation: Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Kuei-Hua
authors.initials: KH
authors.lastname: Chang
authors.forename: Parminder Singh
authors.initials: PS
authors.lastname: Multani
authors.forename: Kai-Hui
authors.initials: KH
authors.lastname: Sun
authors.forename: Fabien
authors.initials: F
authors.lastname: Vincent
authors.forename: Yolanda
authors.initials: Y
authors.lastname: de Pablo
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
authors.forename: Ritika
authors.initials: R
authors.lastname: Gupta
authors.forename: Hyun-Pil
authors.initials: HP
authors.lastname: Lee
authors.forename: Hyoung-Gon
authors.initials: HG
authors.lastname: Lee
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Kavita
authors.initials: K
authors.lastname: Shah
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D016923:Cell Death; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034921:Lamin Type B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016874:Neurofibrillary Tangles; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009685:Nuclear Envelope / Q000201:enzymology*; D034881:Nuclear Lamina / Q000473:pathology; D010766:Phosphorylation; D010770:Phosphotransferases; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; C492236:Cdk5r1 protein, mouse; D034904:Lamin Type A; D034921:Lamin Type B; D009419:Nerve Tissue Proteins; D018698:Glutamic Acid; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases